JPWO2015198505A1 - Method for producing synthetic pentapeptide - Google Patents
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Abstract
工業的に有利に、高純度のペンタペプチドを製造する方法及びその製造中間体の提供。次の式（１）（式中、Ｒ1はアルキル基又はアラルキル基を示す）で表される化合物又はその塩。Industrially advantageously, a method for producing a highly purified pentapeptide and an intermediate for the production thereof. A compound represented by the following formula (1) (wherein R1 represents an alkyl group or an aralkyl group) or a salt thereof.
Description
本発明は、合成ペンタペプチドの製造法及びその製造中間体に関する。 The present invention relates to a method for producing a synthetic pentapeptide and its production intermediate.
κオピオイド受容体アゴニストは、種々の疼痛の治療薬として有用であることが知られている。このうち、末梢κオピオイド受容体に高い選択性を有するκオピオイド受容体アゴニストが、中枢性の副作用を生じない医薬として期待されている。そのような末梢選択性κオピオイド受容体アゴニストとして、合成ペンタペプチドが報告されている（特許文献１及び２）。 Kappa opioid receptor agonists are known to be useful as therapeutic agents for various pains. Among these, κ opioid receptor agonists having high selectivity for peripheral κ opioid receptors are expected as pharmaceuticals that do not cause central side effects. Synthetic pentapeptides have been reported as such peripherally selective κ opioid receptor agonists (Patent Documents 1 and 2).
合成ペンタペプチドの中でも下記式（Ａ） Among synthetic pentapeptides, the following formula (A)
で表される化合物は、疼痛治療薬として有用である。この化合物の製造法としては、上記特許文献１及び２に固相ペプチド合成法が記載されている。 Is useful as a therapeutic agent for pain. As a method for producing this compound, Patent Documents 1 and 2 describe a solid phase peptide synthesis method.
しかしながら、固相ペプチド合成法による製造では、ペンタペプチド保護体を合成後、樹脂からの脱離と全脱保護を行った後、分取ＨＰＬＣにより精製が行なわれている。この精製には大型の分取ＨＰＬＣ装置が必要であり、精製にも長時間を要する。一方、液相法によるペプチド合成も可能であるが、中間工程のペンタペプチド保護体を脱保護した後、化合物（Ａ）を精製しようとしたところ、得られる化合物（Ａ）の純度は８０％未満であり、高純度の化合物（Ａ）は得られないことが判明した。 However, in the production by the solid phase peptide synthesis method, after the pentapeptide protector is synthesized, after desorption from the resin and total deprotection, purification is performed by preparative HPLC. This purification requires a large preparative HPLC apparatus, and it takes a long time for purification. On the other hand, although peptide synthesis by a liquid phase method is also possible, after purifying the compound (A) after deprotecting the pentapeptide protector in the intermediate step, the purity of the compound (A) obtained is less than 80% Thus, it was found that a highly pure compound (A) could not be obtained.
従って、本発明の課題は、高純度の化合物（Ａ）を工業的に有利に製造する方法を提供することにある。 Therefore, the subject of this invention is providing the method of manufacturing a highly purified compound (A) industrially advantageously.
そこで本発明者は、高純度の化合物（Ａ）を製造する方法について検討してきたところ、全く意外にも、化合物（Ａ）のＮ−及びＯ−保護体から、Ｎ−保護基のみを脱離させた下記化合物（１）を単離したところ、当該化合物（１）はスラリー法や再結晶法により高純度に精製可能であり、これを加水分解すれば９０％以上の高純度の化合物（Ａ）が工業的に有利に製造できることを見出し、本発明を完成した。 Therefore, the present inventors have studied a method for producing a high-purity compound (A). Surprisingly, only the N-protecting group is eliminated from the N- and O-protectors of the compound (A). When the following compound (1) was isolated, the compound (1) can be purified to a high purity by a slurry method or a recrystallization method. If this is hydrolyzed, a compound (A) having a purity of 90% or more can be obtained. Was found to be industrially advantageous, and the present invention was completed.
すなわち、本発明は、次の〔１〕〜〔４〕を提供するものである。
〔１〕次の式（１）That is, the present invention provides the following [1] to [4].
[1] The following formula (1)
（式中、Ｒ1はアルキル基又はアラルキル基を示す）
で表される化合物又はその塩。
〔２〕Ｒ1が、アルキル基である〔１〕記載の化合物又はその塩。
〔３〕酸付加塩である〔１〕又は〔２〕記載の化合物又はその塩。
〔４〕〔１〕〜〔３〕のいずれかに記載の化合物又はその塩を加水分解することを特徴とする式（Ａ）(Wherein R 1 represents an alkyl group or an aralkyl group)
Or a salt thereof.
[2] The compound or salt thereof according to [1], wherein R 1 is an alkyl group.
[3] The compound or salt thereof according to [1] or [2], which is an acid addition salt.
[4] Formula (A), wherein the compound or salt thereof according to any one of [1] to [3] is hydrolyzed
で表される化合物又はその塩の製造法。 The manufacturing method of the compound or its salt represented by these.
化合物（１）は、簡便な操作で精製可能であり、当該化合物（１）を加水分解すれば高純度の化合物（Ａ）が工業的に有利に製造可能である。 The compound (1) can be purified by a simple operation. If the compound (1) is hydrolyzed, the high-purity compound (A) can be produced industrially advantageously.
本発明の化合物（１）又はその塩は、化合物（Ａ）の合成中間体として有用である。 The compound (1) or a salt thereof of the present invention is useful as a synthetic intermediate for the compound (A).
式（１）中、Ｒ1はアルキル基又はアラルキル基を示す。アルキル基としては、炭素数１〜１２の直鎖又は分岐鎖のアルキル基が挙げられる。このうち、炭素数１〜８の直鎖又は分岐鎖のアルキル基が好ましく、炭素数１〜４の直鎖又は分岐鎖のアルキル基がより好ましい。当該アルキル基の例としては、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｔｅｒｔ−ブチル基等が挙げられるが、メチル基が特に好ましい。In formula (1), R 1 represents an alkyl group or an aralkyl group. Examples of the alkyl group include linear or branched alkyl groups having 1 to 12 carbon atoms. Among these, a linear or branched alkyl group having 1 to 8 carbon atoms is preferable, and a linear or branched alkyl group having 1 to 4 carbon atoms is more preferable. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, and the like, and a methyl group is particularly preferable.
アラルキル基としては、総炭素数７〜１８のアラルキル基が好ましく、Ｃ6-14アリール−Ｃ1-4アルキル基がより好ましく、フェニル−Ｃ1-4アルキル基がさらに好ましく、ベンジル基が特に好ましい。As the aralkyl group, an aralkyl group having 7 to 18 carbon atoms is preferable, a C 6-14 aryl-C 1-4 alkyl group is more preferable, a phenyl-C 1-4 alkyl group is more preferable, and a benzyl group is particularly preferable. .
前記のＲ1のうち、アルキル基が好ましく、Ｃ1-6アルキル基がより好ましく、Ｃ1-4アルキル基がさらに好ましく、メチル基が特に好ましい。Of the above R 1 , an alkyl group is preferable, a C 1-6 alkyl group is more preferable, a C 1-4 alkyl group is further preferable, and a methyl group is particularly preferable.
また、化合物（１）の塩としては、酸付加塩が挙げられ、具体的には塩酸塩、硫酸塩、硝酸塩等の無機酸塩；酢酸塩、トリフルオロ酢酸塩等の有機酸塩が挙げられ、無機酸塩としては塩酸塩が好ましく、有機酸塩としてはトリフルオロ酢酸塩が好ましい。このうち塩酸塩がより好ましい。 The salt of compound (1) includes acid addition salts, specifically, inorganic acid salts such as hydrochlorides, sulfates and nitrates; organic acid salts such as acetates and trifluoroacetates. As the inorganic acid salt, hydrochloride is preferable, and as the organic acid salt, trifluoroacetate is preferable. Of these, hydrochloride is more preferable.
化合物（１）及びその塩のうち、結晶の形態で単離が容易であり、精製が容易である点で、Ｒ1がＣ1-6アルキル基である化合物（１）の塩が好ましく、Ｒ1がＣ1-6アルキル基である化合物（１）の酸付加塩がより好ましく、Ｒ1がＣ1-4アルキル基である化合物（１）の酸付加塩がさらに好ましく、Ｒ1がメチル基である化合物（１）の酸付加塩が特に好ましい。Of the compound (1) and a salt thereof, a salt of the compound (1) in which R 1 is a C 1-6 alkyl group is preferable in that it can be easily isolated in a crystalline form and easily purified. An acid addition salt of compound (1) wherein 1 is a C 1-6 alkyl group is more preferred, an acid addition salt of compound (1) wherein R 1 is a C 1-4 alkyl group is more preferred, and R 1 is a methyl group The acid addition salt of compound (1) is particularly preferred.
化合物（１）又はその塩及び化合物（Ａ）は、例えば次の反応式に示すように、４−アミノピペリジン−４−カルボン酸、Ｄ−リジン（Ｄ−Ｌｙｓ）、Ｄ−ロイシン（Ｄ−Ｌｅｕ）、Ｄ−フェニルアラニン（Ｄ−Ｐｈｅ）及びＤ−フェニルアラニン（Ｄ−Ｐｈｅ）を順次縮合させる液相ペプチド合成法により製造することができる。 The compound (1) or a salt thereof and the compound (A) can be synthesized, for example, as shown in the following reaction formula: 4-aminopiperidine-4-carboxylic acid, D-lysine (D-Lys), D-leucine (D-Leu). ), D-phenylalanine (D-Phe) and D-phenylalanine (D-Phe) can be produced by a liquid phase peptide synthesis method.
（式中、Ｐ1及びＰ2はそれぞれＮ−保護基を示し、Ｒ1は前記と同じである）(Wherein P 1 and P 2 each represent an N-protecting group, and R 1 is the same as above)
上記反応式中、Ｐ1及びＰ2で示されるＮ−保護基は、それぞれ異なる脱離手段で脱離できる保護基が好ましい。これらの保護基としては、（１）酸で脱離できる保護基（例えば、ｔｅｒｔ−ブトキシカルボニル基（Ｂｏｃ）、ｐ-メトキシベンジルオキシカルボニル基(Ｍｏｚ)、ホルミル基(ＣＨＯ)、２-(トリメチルシリル)エトキシカルボニル基(Ｔｅｏｃ)、１-アダマンチルオキシカルボニル基(Ａｄｏｃ)、２−（ｐ−ビフェニル）イソプロピルオキシカルボニル基(Ｂｐｏｃ)、トリフェニルメチル基(Ｔｒ)、メトキシメチル基(ＭＯＭ)）；（２）還元で脱離できる保護基（例えば、ベンジルオキシカルボニル基（Ｃｂｚ）、アリル基(Ａｌｌｙｌ)、Ｎ-ベンジルオキシメチル基(ＢＯＭ)）；（３）二級アミンで脱離できる保護基（例えば、９−フルオレニルメチルオキシカルボニル基（Ｆｍｏｃ）、２−（４−ニトロフェニル)エトキシカルボニル基(Ｎｐｅｏｃ)）；（４）亜鉛末−酢酸などで脱離できる保護基（例えば、２，２，２−トリクロロエトキシカルボニル基（Ｔｒｏｃ）、Ｎ-ジチアスクシノイル基(Ｄｔｓ)、ベンゾチアゾール-２-スルホニル基(Ｂｅｔｓｙｌ)、１,１-ジメチル-２,２,２-トリクロロエトキシカルボニル基(ＴｃＢｏｃ)、Ｎ-(ジフェニル-４-ピリジル)メチル基(Ｄｐｐｍ)）；（５）パラジウム触媒下、アミンなどで脱離できる保護基（例えば、アリルオキシカルボニル基（Ａｌｌｏｃ））等が挙げられる。Ｐ1及びＰ2として、これらの保護基のうち、脱離条件が異なるものを選択して用いればよい。例えばＰ1としては、Ｂｏｃが好ましく、Ｐ2としてはＣｂｚが好ましい。In the above reaction formulas, the N-protecting groups represented by P 1 and P 2 are preferably protecting groups that can be removed by different leaving means. These protecting groups include (1) protecting groups that can be removed by acid (for example, tert-butoxycarbonyl group (Boc), p-methoxybenzyloxycarbonyl group (Moz), formyl group (CHO), 2- (trimethylsilyl). ) Ethoxycarbonyl group (Teoc), 1-adamantyloxycarbonyl group (Adoc), 2- (p-biphenyl) isopropyloxycarbonyl group (Bpoc), triphenylmethyl group (Tr), methoxymethyl group (MOM)); 2) Protecting groups that can be removed by reduction (for example, benzyloxycarbonyl group (Cbz), allyl group (Allyl), N-benzyloxymethyl group (BOM)); (3) Protecting groups that can be removed by secondary amines ( For example, 9-fluorenylmethyloxycarbonyl group (Fmoc), 2- (4-nitrophenyl) ethoxycarbonyl group (Npeo) )); (4) Protecting groups that can be removed with zinc dust-acetic acid (eg, 2,2,2-trichloroethoxycarbonyl group (Troc), N-dithiasuccinoyl group (Dts), benzothiazole-2- Sulfonyl group (Betsyl), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl group (TcBoc), N- (diphenyl-4-pyridyl) methyl group (Dppm)); (5) amine under palladium catalyst And the like (eg, allyloxycarbonyl group (Alloc)) and the like which can be eliminated by, for example. P 1 and P 2 may be selected from those protecting groups having different elimination conditions. For example, B 1 is preferable as P 1 , and Cbz is preferable as P 2 .
化合物（２）と保護Ｄ−Ｌｅｕとの縮合、化合物（４）と保護Ｄ−Ｌｅｕとの縮合、化合物（６）と保護Ｄ−Ｐｈｅとの縮合、及び化合物（８）と保護Ｄ−Ｐｈｅとの縮合反応は、例えばモレキュラーシーブ、１−ヒドロキシベンゾトリアゾール（ＨＯＢｔ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド塩酸塩（ＥＤＣ・ＨＣｌ）、Ｎ，Ｎ−ジシクロヘキシルカルボジイミド（ＤＣＣ）等の縮合剤の存在下に行うことができる。具体的には、縮合剤の存在下、ハロゲン系、エステル系またはエーテル系等の溶媒中、０〜４０℃で１〜４８時間反応により行うことができる。 Condensation of compound (2) with protected D-Leu, condensation of compound (4) with protected D-Leu, condensation of compound (6) with protected D-Phe, and compound (8) with protected D-Phe Examples of the condensation reaction include molecular sieve, 1-hydroxybenzotriazole (HOBt), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl), N, N-dicyclohexylcarbodiimide (DCC), etc. In the presence of a condensing agent. Specifically, the reaction can be carried out in the presence of a condensing agent in a halogen-based, ester-based or ether-based solvent at 0 to 40 ° C. for 1 to 48 hours.
また、脱保護反応は、前記の保護基の種類に応じた方法を選択して行うことができる。化合物（１）を塩酸塩等の酸付加塩として得るためには、Ｐ1として酸で脱離できる保護基（例えばＢｏｃ）を選択するのが好ましく、Ｐ2として還元で脱離できる保護基（例えば（Ｃｂｚ））を選択するのが好ましい。Ｐ1としてＢｏｃを用いた場合、例えば酸を用いる加水分解によりＰ1を脱保護すれば、化合物（１）の酸付加塩が得られる。還元による脱保護は、例えば、金属触媒の存在下、エステル系またはエーテル系等の溶媒中、０〜４０℃、１〜４８時間反応により行うことができる。酸による脱保護は、例えば無機酸やトリフルオロ酢酸等の存在下、エステル系またはエーテル系等の溶媒中、０〜４０℃、１〜４８時間反応により行うことができる。The deprotection reaction can be carried out by selecting a method according to the kind of the protecting group. In order to obtain the compound (1) as an acid addition salt such as hydrochloride, it is preferable to select a protecting group (for example, Boc) that can be eliminated with an acid as P 1 , and a protecting group that can be eliminated by reduction as P 2 ( For example, it is preferable to select (Cbz)). When Boc is used as P 1 , for example, if P 1 is deprotected by hydrolysis using an acid, an acid addition salt of compound (1) can be obtained. Deprotection by reduction can be performed, for example, by reaction in an ester-based or ether-based solvent at 0 to 40 ° C. for 1 to 48 hours in the presence of a metal catalyst. Deprotection with an acid can be carried out by reaction in an ester or ether solvent in the presence of an inorganic acid or trifluoroacetic acid, for example, at 0 to 40 ° C. for 1 to 48 hours.
化合物（１）の塩は、再結晶などにより容易に精製できる。また化合物（１）の塩は、精製しなくても十分高純度である。従って、化合物（１）の塩を加水分解すれば、高純度の化合物（Ａ）が製造できる。ここで加水分解反応は、例えば塩基の存在下に行うのが好ましい。具体的には、水酸化ナトリウム等の存在下、水やアルコール系等の溶媒中、０〜４０℃、１〜４８時間反応により行うことができる。 The salt of compound (1) can be easily purified by recrystallization or the like. Further, the salt of compound (1) is sufficiently pure even without purification. Therefore, high purity compound (A) can be produced by hydrolyzing the salt of compound (1). Here, the hydrolysis reaction is preferably performed in the presence of a base, for example. Specifically, it can be carried out by reaction in a solvent such as water or alcohol in the presence of sodium hydroxide or the like at 0 to 40 ° C. for 1 to 48 hours.
本発明方法（液相法）による化合物（Ａ）の製造法によれば、固相合成法に比べ、ジアステレオマーや欠損ペプチドといった除去困難な不純物が生じにくく、またできたとしても、中間工程で除去できる。また、固相合成法に比べ、中間体化合物を単離できるため、スラリー法や再結晶法など、操作が比較的容易で高価な設備投資を要しない濾過的精製法が実施可能であり、例えばＨＰＬＣ測定で純度９９％の高純度の目的物を得ることが容易である。
固相合成法では、塩化メチレンやジメチルホルムアミド等、使用する溶媒が限定されるのに比べ、液相合成法では、工業化に適した安全で安価な溶媒を使用することが可能である。固相合成法に比べ、大量合成が容易である。固相合成法では最終化合物の精製に「分取ＨＰＬＣ法」（一般的に高額の設備、大量の有機溶媒を要する）を要することが多いが、液相合成法ではこれらの問題を回避することができる。According to the production method of the compound (A) by the method of the present invention (liquid phase method), it is difficult to produce impurities that are difficult to remove such as diastereomers and defective peptides as compared with the solid phase synthesis method. Can be removed. Further, since the intermediate compound can be isolated as compared with the solid phase synthesis method, it is possible to implement a filtration purification method that is relatively easy to operate and does not require expensive capital investment, such as a slurry method and a recrystallization method. It is easy to obtain a highly pure target product having a purity of 99% by HPLC measurement.
In the solid phase synthesis method, the solvent to be used is limited, such as methylene chloride and dimethylformamide, but in the liquid phase synthesis method, a safe and inexpensive solvent suitable for industrialization can be used. Large-scale synthesis is easier than solid-phase synthesis. Solid-phase synthesis often requires “preparative HPLC” (generally expensive equipment and large amounts of organic solvent) to purify the final compound, but liquid-phase synthesis avoids these problems. Can do.
次に実施例を挙げて本発明を更に詳細に説明する。 EXAMPLES Next, an Example is given and this invention is demonstrated still in detail.
実施例１
（１）Ｃｂｚ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（３）の合成
２Ｌの４つ口フラスコに、α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ・ＨＣｌ[α−Ｂｏｃ−４−アミノピペリジン−４−カルボン酸メチル塩酸塩]（２）４３．７ｇ（１４８ｍｍｏｌ）を仕込み、ＥｔＯＡｃ ６５６ｍＬ（１５ｖ／ｗ）に懸濁させた。この懸濁液に１−ヒドロキシベンゾトリアゾール（ＨＯＢｔ）２７．２ｇ（１７８ｍｍｏｌ）、Ｃｂｚ−Ｄ−Ｌｙｓ（Ｂｏｃ）−ＯＨ ５９．２ｇ（１５６ｍｍｏｌ）を加え氷浴にて冷却しながら１−エチル−３−（３−ジメチアミノプロピル）カルボジイミド・ＨＣｌ（ＥＤＣ・ＨＣｌ）３４．１ｇ（１７８ｍｍｏｌ）を添加した。２０分後、室温に昇温し１２時間撹拌した。反応終了後、１Ｎ ＨＣｌ ２１８ｍＬ（５．０ｖ／ｗ）を加え有機層を分液した。得られた有機層にＮａＨＣＯ3ａｑ．２１８ｍＬ（５．０ｖ／ｗ）、Ｅｔ3Ｎ ３３．０ｇ（３２６ｍｍｏｌ）を加え３０分撹拌して、分液した。有機層を１Ｎ ＨＣｌ ２１８ｍＬ（５．０ｖ／ｗ）、ＮａＨＣＯ3ａｑ．２１８ｍＬ（５．０ｖ／ｗ）、ＮａＣｌａｑ．２１８ｍＬ（５．０ｖ／ｗ）で順次洗浄し、Ｎａ2ＳＯ4 ８．７４ｇ（０．２ｗ／ｗ）を加え乾燥させた。減圧濾過を行い、得られた濾液をエバポレーターにて減圧濃縮後、真空ポンプでポンプアップし、Ｃｂｚ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（３）８８．９ｇを白色固体として得た（収率９６．５％、ＨＰＬＣ純度９６．５％）。Example 1
(1) Synthesis of Cbz-D-Lys (Boc) -α-Boc-Pic-OMe (3) In a 2 L four-necked flask, α-Boc-Pic-OMe · HCl [α-Boc-4-aminopiperidine -4-Carboxylic acid methyl hydrochloride] (2) 43.7 g (148 mmol) was charged and suspended in 656 mL (15 v / w) of EtOAc. To this suspension, 27.2 g (178 mmol) of 1-hydroxybenzotriazole (HOBt) and 59.2 g (156 mmol) of Cbz-D-Lys (Boc) -OH were added while cooling in an ice bath. -(3-Dimethylaminopropyl) carbodiimide.HCl (EDC.HCl) 34.1 g (178 mmol) was added. After 20 minutes, the temperature was raised to room temperature and stirred for 12 hours. After completion of the reaction, 218 mL (5.0 v / w) of 1N HCl was added to separate the organic layer. To the obtained organic layer, NaHCO 3 aq. 218 mL (5.0 v / w) and Et 3 N 33.0 g (326 mmol) were added, and the mixture was stirred for 30 minutes and separated. The organic layer was washed with 218 mL of 1N HCl (5.0 v / w), NaHCO 3 aq. 218 mL (5.0 v / w), NaClaq. Washed sequentially with 218mL (5.0v / w), dried adding Na 2 SO 4 8.74g (0.2w / w). After filtration under reduced pressure, the obtained filtrate was concentrated under reduced pressure with an evaporator, and then pumped up with a vacuum pump to obtain 88.9 g of Cbz-D-Lys (Boc) -α-Boc-Pic-OMe (3) as a white solid. Obtained (yield 96.5%, HPLC purity 96.5%).
（２）Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（４）の合成
２Ｌのナスフラスコに、Ｃｂｚ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（３）８８．３ｇ（１４２ｍｍｏｌ）を仕込み、ＥｔＯＡｃを４４１ｍＬ（５．０ｖ／ｗ）加え溶解させた。反応液に５％Ｐｄ／Ｃを１７．７ｇ（０．２ｗ／ｗ）加え、減圧雰囲気下窒素置換を３回行った後、水素置換を３回行った。反応溶液を室温で１８時間激しく撹拌し、反応終了後減圧濾過してＰｄ／Ｃを除去した。得られた濾液にＮａＨＣＯ3ａｑ．４４１ｍＬ（５．０ｖ／ｗ）を加え分液し、水層にＥｔＯＡｃ ２００ｍＬ（２．３ｖ／ｗ）を加えて有機層を抽出した。合わせた有機層にＮａＨＣＯ3ａｑ．４４１ｍＬ（５．０ｖ／ｗ）を加え分液し、水層にＥｔＯＡｃ ２００ｍＬ（２．３ｖ／ｗ）を加え有機層を抽出した。合わせた有機層にＮａＣｌａｑ．４４１ｍＬ（５．０ｖ／ｗ）を加えて分液し、水層にＥｔＯＡｃ ２００ｍＬ（２．３ｖ／ｗ）を加えて抽出した。合わせた有機層にＮａ2ＳＯ4 １７．７ｇ（０．２ｗ／ｗ）を加え乾燥させ、減圧濾過を行い得た濾液をエバポレーターにて減圧濃縮させ、真空ポンプでポンプアップし、Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（４）を６２．７ｇ得た（収率９０．５％、ＨＰＬＣ純度９３．６％）。(2) Synthesis of D-Lys (Boc) -α-Boc-Pic-OMe (4) In a 2 L eggplant flask, Cbz-D-Lys (Boc) -α-Boc-Pic-OMe (3) 88.3 g (142 mmol) was charged, and 441 mL (5.0 v / w) of EtOAc was added and dissolved. 17.7 g (0.2 w / w) of 5% Pd / C was added to the reaction solution, and after nitrogen substitution was performed three times in a reduced pressure atmosphere, hydrogen substitution was performed three times. The reaction solution was vigorously stirred at room temperature for 18 hours, and after completion of the reaction, Pd / C was removed by filtration under reduced pressure. To the obtained filtrate was added NaHCO 3 aq. 441 mL (5.0 v / w) was added for liquid separation, and 200 mL of EtOAc (2.3 v / w) was added to the aqueous layer to extract the organic layer. To the combined organic layer was added NaHCO 3 aq. 441 mL (5.0 v / w) was added for liquid separation, and 200 mL of EtOAc (2.3 v / w) was added to the aqueous layer to extract the organic layer. NaClaq. Was added to the combined organic layers. 441 mL (5.0 v / w) was added for liquid separation, and 200 mL of EtOAc (2.3 v / w) was added to the aqueous layer for extraction. The combined organic layers were dried by adding 17.7 g (0.2 w / w) of Na 2 SO 4 , and the filtrate obtained by filtration under reduced pressure was concentrated under reduced pressure with an evaporator, pumped up with a vacuum pump, and D-Lys ( Boc) -α-Boc-Pic-OMe (4) (62.7 g) was obtained (yield 90.5%, HPLC purity 93.6%).
（３）Ｃｂｚ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（５）の合成
２Ｌの４つ口フラスコに、Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（４）５７．７ｇ（１２０ｍｍｏｌ）を仕込み、ＥｔＯＡｃ ５７６ｍＬ（１０ｖ／ｗ）に懸濁させた。この懸濁液にＨＯＢｔ １９．３ｇ（１２６ｍｍｏｌ）、Ｃｂｚ−Ｄ−Ｌｅｕ−ＯＨ ３３．４ｇ（１２６ｍｍｏｌ）を加え氷浴にて冷却しながらＥＤＣ・ＨＣｌ ２４．２ｇ（１２６ｍｍｏｌ）を添加した。２０分後、室温に昇温し５時間撹拌した後、さらにＥＤＣ・ＨＣｌを１．１５ｇ（６．００ｍｍｏｌ）添加して１６時間撹拌した。反応終了後、１Ｎ ＨＣｌ ５７６ｍＬ（１０ｖ／ｗ）を加え分液した。得られた有機層にＮａＨＣＯ3ａｑ．５７６ｍＬ（１０ｖ／ｗ）、Ｅｔ3Ｎ ２４．３ｇ（２４０ｍｍｏｌ）を加え３０分撹拌して、分液した。有機層を１Ｎ ＨＣｌ ５７６ｍＬ（１０ｖ／ｗ）、ＮａＨＣＯ3ａｑ．５７６ｍＬ（１０ｖ／ｗ）、ＮａＣｌａｑ．５７６ｍＬ（１０ｖ／ｗ）で順次洗浄し、Ｎａ2ＳＯ4 １１．５ｇ（０．２ｗ／ｗ）を加え乾燥させた。減圧濾過を行い得られた濾液をエバポレーターにて減圧濃縮後、真空ポンプでポンプアップし、Ｃｂｚ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（５）８５．８ｇを白色固体として得た（収率９８．７％、ＨＰＬＣ純度９６．９％）。(3) Synthesis of Cbz-D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe (5) In a 2 L 4-neck flask, D-Lys (Boc) -α-Boc-Pic-OMe (4) 57.7 g (120 mmol) was charged and suspended in 576 mL (10 v / w) of EtOAc. To this suspension, 19.3 g (126 mmol) of HOBt and 33.4 g (126 mmol) of Cbz-D-Leu-OH were added, and 24.2 g (126 mmol) of EDC · HCl was added while cooling in an ice bath. After 20 minutes, the mixture was warmed to room temperature and stirred for 5 hours, and then 1.15 g (6.00 mmol) of EDC · HCl was further added and stirred for 16 hours. After completion of the reaction, 576 mL (10 v / w) of 1N HCl was added to separate the layers. To the obtained organic layer, NaHCO 3 aq. 576mL (10v / w), Et 3 N 24.3g (240mmol) was stirred for 30 minutes, and the mixture was separated. The organic layer was washed with 576 mL of 1N HCl (10 v / w), NaHCO 3 aq. 576 mL (10 v / w), NaClaq. The mixture was washed sequentially with 576 mL (10 v / w), and 11.5 g (0.2 w / w) of Na 2 SO 4 was added and dried. The filtrate obtained by filtration under reduced pressure was concentrated under reduced pressure with an evaporator and then pumped up with a vacuum pump to obtain 85.8 g of Cbz-D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe (5). Obtained as a white solid (yield 98.7%, HPLC purity 96.9%).
（４）Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（６）の合成
１Ｌのナスフラスコに、Ｃｂｚ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（５）を９１．９ｇ（１２５ｍｍｏｌ）仕込み、ＥｔＯＡｃを４５９ｍＬ（５．０ｖ／ｗ）加え溶解させた。反応液に５％Ｐｄ／Ｃを１８．４ｇ（０．２ｗ／ｗ）加え、減圧雰囲気下窒素置換を３回行った後、水素置換を３回行った。反応溶液を室温で８時間激しく撹拌を行い、反応終了後減圧濾過してＰｄ／Ｃを除去した。得られた濾液にＮａＨＣＯ3ａｑ．２００ｍＬ（２．２ｖ／ｗ）を加え分液し、有機層にＮａＨＣＯ3ａｑ．２００ｍＬ（２．２ｖ／ｗ）、ＮａＣｌａｑ．２００ｍＬ（２．２ｖ／ｗ）を順次加え洗浄した。得られた有機層にＮａ2ＳＯ4 １８．４ｇ（０．２ｗ／ｗ）を加え乾燥させ、減圧濾過を行い得た濾液をエバポレーターにて減圧濃縮させ、真空ポンプでポンプアップした。得られたアモルファス状の固体にＥｔＯＡｃ ２００ｍＬ（２．２ｖ／ｗ）を加え溶解させ、ヘプタン５０ｍＬ（１．８ｖ／ｗ）を加えて晶析させた。減圧濾過して析出結晶を濾別し、ＥｔＯＡｃ １２０ｍＬ（１．３ｖ／ｗ）、ヘプタン５０ｍＬ（０．３ｖ／ｗ）の混合溶媒で結晶を洗浄した。得られた結晶４６．１ｇにＥｔＯＡｃ ４８０ｍＬ（５．２ｖ／ｗ）を加え溶解させ、シクロヘキサン６６０ｍＬ（７．２ｖ／ｗ）を加え晶析させた。減圧濾過して析出結晶を濾別し、シクロヘキサン１２０ｍＬ（１．３ｖ／ｗ）、ＥｔＯＡｃ ２０ｍＬ（０．２ｖ／ｗ）の混合溶媒で洗浄し、３０℃減圧乾燥し、白色固体としてＤ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（６）を３６．６ｇ得た（収率４８．７％、ＨＰＬＣ純度９９．９％）。(4) Synthesis of D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe (6) Into a 1 L eggplant flask, Cbz-D-Leu-D-Lys (Boc) -α-Boc-Pic -91.9 g (125 mmol) of -OMe (5) was charged, and 459 mL (5.0 v / w) of EtOAc was added and dissolved. 18.4 g (0.2 w / w) of 5% Pd / C was added to the reaction solution, and after nitrogen substitution was performed three times in a reduced pressure atmosphere, hydrogen substitution was performed three times. The reaction solution was vigorously stirred at room temperature for 8 hours, and after completion of the reaction, vacuum filtration was performed to remove Pd / C. To the obtained filtrate was added NaHCO 3 aq. 200 mL (2.2 v / w) was added for liquid separation, and NaHCO 3 aq. 200 mL (2.2 v / w), NaClaq. 200 mL (2.2 v / w) was sequentially added and washed. To the obtained organic layer, 18.4 g (0.2 w / w) of Na 2 SO 4 was added and dried, and the filtrate obtained by filtration under reduced pressure was concentrated under reduced pressure with an evaporator and pumped up with a vacuum pump. To the obtained amorphous solid, 200 mL (2.2 v / w) of EtOAc was added and dissolved, and 50 mL (1.8 v / w) of heptane was added to cause crystallization. The crystals were separated by filtration under reduced pressure, and the crystals were washed with a mixed solvent of 120 mL (1.3 v / w) of EtOAc and 50 mL (0.3 v / w) of heptane. To 46.1 g of the obtained crystal, 480 mL (5.2 v / w) of EtOAc was added and dissolved, and 660 mL (7.2 v / w) of cyclohexane was added for crystallization. The crystals were separated by filtration under reduced pressure, washed with a mixed solvent of 120 mL (1.3 v / w) of cyclohexane and 20 mL (0.2 v / w) of cyclohexane, dried at 30 ° C. under reduced pressure, and D-Leu- as a white solid. 36.6 g of D-Lys (Boc) -α-Boc-Pic-OMe (6) was obtained (yield 48.7%, HPLC purity 99.9%).
（５）Ｃｂｚ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（７）の合成
１Ｌの４つ口フラスコに、Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（６）を３５．８ｇ（５９．６ｍｍｏｌ）仕込み、ＥｔＯＡｃ ３５８ｍＬ（１０ｖ／ｗ）に懸濁させた。この懸濁液にＨＯＢｔ ９．５９ｇ（６２．６ｍｍｏｌ）、Ｃｂｚ−Ｄ−Ｐｈｅ−ＯＨ １８．７ｇ（６２．６ｍｍｏｌ）を加え氷浴にて冷却しながらＥＤＣ・ＨＣｌ １２．０ｇ（６２．６ｍｍｏｌ）を添加した。２０分後、室温に昇温し１６時間撹拌した後さらにＥＤＣ・ＨＣｌを３．０９ｇ（１６．１ｍｍｏｌ）添加した。反応終了後、１Ｎ ＨＣｌ ３５８ｍＬ（１０ｖ／ｗ）を加え有機層を分液した。得られた有機層にＮａＨＣＯ3ａｑ．３５８ｍＬ（１０ｖ／ｗ）、Ｅｔ3Ｎ １２．１ｇ（１１９ｍｍｏｌ）を加え３０分撹拌して、分液した。有機層を１Ｎ ＨＣｌ ３５８ｍＬ（１０ｖ／ｗ）、ＮａＨＣＯ3ａｑ．３５８ｍＬ（１０ｖ／ｗ）、ＮａＣｌａｑ．３５８ｍＬ（１０ｖ／ｗ）で順次洗浄し、Ｎａ2ＳＯ4 ７．１６ｇ（０．２ｗ／ｗ）を加え乾燥させた。減圧濾過を行い得た濾液をエバポレーターにて減圧濃縮後、真空ポンプでポンプアップし、Ｃｂｚ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（７）を白色固体として５２．５ｇ得た（収率ｑｕａｎｔ、ＨＰＬＣ純度９７．６％）。(5) Synthesis of Cbz-D-Phe-D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe (7) In a 1 L four-necked flask, D-Leu-D-Lys (Boc) -35.8 g (59.6 mmol) of α-Boc-Pic-OMe (6) was charged and suspended in 358 mL (10 v / w) of EtOAc. To this suspension were added 9.59 g (62.6 mmol) of HOBt and 18.7 g (62.6 mmol) of Cbz-D-Phe-OH, and 12.0 g (62.6 mmol) of EDC · HCl while cooling in an ice bath. Was added. After 20 minutes, the temperature was raised to room temperature and stirred for 16 hours, and then 3.09 g (16.1 mmol) of EDC · HCl was further added. After completion of the reaction, 358 mL (10 v / w) of 1N HCl was added, and the organic layer was separated. To the obtained organic layer, NaHCO 3 aq. 358 mL (10 v / w) and Et 3 N 12.1 g (119 mmol) were added, and the mixture was stirred for 30 minutes and separated. The organic layer was washed with 358 mL of 1N HCl (10 v / w), NaHCO 3 aq. 358 mL (10 v / w), NaClaq. This was sequentially washed with 358 mL (10 v / w), 7.16 g (0.2 w / w) of Na 2 SO 4 was added and dried. The filtrate obtained by filtration under reduced pressure was concentrated under reduced pressure with an evaporator and then pumped up with a vacuum pump to obtain Cbz-D-Phe-D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe (7). 52.5 g was obtained as a white solid (yield quant, HPLC purity 97.6%).
（６）Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（８）の合成
２Ｌのナスフラスコに、Ｃｂｚ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（７）を４６．９ｇ（５３．３ｍｍｏｌ）仕込み、ＥｔＯＡｃを８４０ｍＬ（１８ｖ／ｗ）、Ｈ2Ｏ ９３．８ｍＬ（２．０ｖ／ｗ）を加え溶解させた。反応液に５％ Ｐｄ／Ｃを９．３８ｇ（０．２ｗ／ｗ）加え、減圧雰囲気下窒素置換を３回行った後、水素置換を３回行った。反応溶液を室温で１０時間激しく撹拌を行い、反応終了後減圧濾過してＰｄ／Ｃを除去した。得られた濾液にＮａＨＣＯ3ａｑ．２３５ｍＬ（５．０ｖ／ｗ）を加え分液し、有機層にＮａＨＣＯ3ａｑ．２３５ｍＬ（５．０ｖ／ｗ）、ＮａＣｌａｑ．２３５ｍＬ（５．０ｖ／ｗ）を順次加え洗浄した。得られた有機層にＮａ2ＳＯ4 ９．３８ｇ（０．２ｗ／ｗ）を加え乾燥させ、減圧濾過を行い得た濾液をエバポレーターにて減圧濃縮させ、真空ポンプでポンプアップしてＤ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（７）を３９．７ｇ得た（収率ｑｕａｎｔ、ＨＰＬＣ純度９７．３％）。(6) Synthesis of D-Phe-D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe (8) To a 2 L eggplant flask, Cbz-D-Phe-D-Leu-D-Lys ( Boc) -α-Boc-Pic-OMe (7) is charged with 46.9 g (53.3 mmol), and 840 mL (18 v / w) of EtOAc and 93.8 mL (2.0 v / w) of H 2 O are added and dissolved. It was. 9.38 g (0.2 w / w) of 5% Pd / C was added to the reaction solution, and after nitrogen substitution was performed three times in a reduced pressure atmosphere, hydrogen substitution was performed three times. The reaction solution was vigorously stirred at room temperature for 10 hours, and after completion of the reaction, vacuum filtration was performed to remove Pd / C. To the obtained filtrate was added NaHCO 3 aq. 235 mL (5.0 v / w) was added for liquid separation, and NaHCO 3 aq. 235 mL (5.0 v / w), NaClaq. 235 mL (5.0 v / w) was sequentially added and washed. To the obtained organic layer, 9.38 g (0.2 w / w) of Na 2 SO 4 was added and dried, and the filtrate obtained by filtration under reduced pressure was concentrated under reduced pressure with an evaporator, pumped up with a vacuum pump, and D-Phe. -39.7g of -D-Leu-D-Lys (Boc)-(alpha) -Boc-Pic-OMe (7) was obtained (yield quant, HPLC purity 97.3%).
（７）Ｂｏｃ−Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（９）の合成
１Ｌの４つ口フラスコに、Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（８）を３５．１ｇ仕込み、ＥｔＯＡｃ ３５１ｍＬ（１０ｖ／ｗ）に懸濁させた。この懸濁液にＨＯＢｔ ７．９２ｇ（５１．７ｍｍｏｌ）、Ｂｏｃ−Ｄ−Ｐｈｅ−ＯＨ １３．１ｇ（４９．４ｍｍｏｌ）を加え氷浴にて冷却しながらＥＤＣ・ＨＣｌ ９．９１ｇ（５１．７ｍｍｏｌ）を添加した。２０分後、室温に昇温し８時間撹拌後さらにＥＤＣ・ＨＣｌを２．２５ｇ（１１．７ｍｍｏｌ）添加した。反応終了後、１Ｎ ＨＣｌ ３５１ｍＬ（１０ｖ／ｗ）を加え有機層を分液した。得られた有機層にＮａＨＣＯ3ａｑ．３５１ｍＬ（１０ｖ／ｗ）、Ｅｔ3Ｎ ９．５１ｇ（９４．０ｍｍｏｌ）を加え３０分撹拌して、分液した。有機層を１Ｎ ＨＣｌ ３５１ｍＬ（１０ｖ／ｗ）、ＮａＨＣＯ3ａｑ．３５１ｍＬ（１０ｖ／ｗ）、ＮａＣｌａｑ．３５１ｍＬ（１０ｖ／ｗ）で順次洗浄し、Ｎａ2ＳＯ4 ７．０２ｇ（０．２ｗ／ｗ）を加え乾燥させた。減圧濾過を行い得た濾液をエバポレーターにて減圧濃縮後、真空ポンプでポンプアップし、Ｂｏｃ−Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（９）を白色固体として４６．７ｇ得た（収率ｑｕａｎｔ、ＨＰＬＣ純度９８．６％）。(7) Synthesis of Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe (9) In a 1 L four-necked flask, D-Phe-D- 35.1 g of Leu-D-Lys (Boc) -α-Boc-Pic-OMe (8) was charged and suspended in 351 mL (10 v / w) of EtOAc. To this suspension were added 7.92 g (51.7 mmol) of HOBt and 13.1 g (49.4 mmol) of Boc-D-Phe-OH, and 9.91 g (51.7 mmol) of EDC · HCl while cooling in an ice bath. Was added. After 20 minutes, the temperature was raised to room temperature and stirred for 8 hours, and then 2.25 g (11.7 mmol) of EDC · HCl was added. After completion of the reaction, 351 mL (10 v / w) of 1N HCl was added, and the organic layer was separated. To the obtained organic layer, NaHCO 3 aq. 351 mL (10 v / w) and Et 3 N 9.51 g (94.0 mmol) were added, and the mixture was stirred for 30 minutes and separated. The organic layer was washed with 351 mL of 1N HCl (10 v / w), NaHCO 3 aq. 351 mL (10 v / w), NaClaq. The resultant was washed successively with 351 mL (10 v / w), 7.02 g (0.2 w / w) of Na 2 SO 4 was added and dried. The filtrate obtained by filtration under reduced pressure was concentrated under reduced pressure with an evaporator, and then pumped up with a vacuum pump. Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe 46.7 g of (9) was obtained as a white solid (yield quant, HPLC purity 98.6%).
（８）Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ塩酸塩（１）の合成
２０ｍＬのナスフラスコにＢｏｃ−Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（９）を２．００ｇ仕込み、ＩＰＡ ３．３ｍＬ（１．６５ｖ／ｗ）、ＰｈＭｅ １０ｍＬ（５ｖ／ｗ）を加えて懸濁させた。６Ｎ ＨＣｌ／ＩＰＡ ６．７ｍＬ（３．３５ｖ／ｗ）を加えて室温で１９時間撹拌した。析出した固体を減圧濾過で濾別し、減圧乾燥して白色固体のＤ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ塩酸塩（１）を１．５９ｇ（収率９９．０％、ＨＰＬＣ純度９８．２％）得た。(8) Synthesis of D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe Hydrochloride (1) In a 20 mL eggplant flask, Boc-D-Phe-D-Phe-D-Leu-D- 2.00 g of Lys (Boc) -α-Boc-Pic-OMe (9) was charged, and IPA 3.3 mL (1.65 v / w) and PhMe 10 mL (5 v / w) were added and suspended. 6.7 mL (3.35 v / w) of 6N HCl / IPA was added and stirred at room temperature for 19 hours. The precipitated solid was separated by filtration under reduced pressure, dried under reduced pressure, and 1.59 g (99% yield) of white solid D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe hydrochloride (1). 0.0%, HPLC purity 98.2%).
（９）Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ塩酸塩（１）の精製
２０ｍＬのナスフラスコにＤ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ塩酸塩粗晶（１）２００ｍｇを仕込み、ＥｔＯＨ：ＭｅＣＮ＝１：５の混合溶媒４．０ｍＬ（２０ｖ／ｗ）を加え４０℃に加熱して１時間撹拌した後、さらに室温で２時間撹拌スラリーした。減圧濾過して濾別し、得られた固体を減圧乾燥して白色固体（（１）精製晶）を１６１ｍｇ得た（収率８０％、ＨＰＬＣ純度９９．２％）。(9) Purification of D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe hydrochloride (1) In a 20 mL eggplant flask, D-Phe-D-Phe-D-Leu-D-Lys- 200 mg of Pic-OMe hydrochloride crude crystal (1) was charged, 4.0 mL (20 v / w) of a mixed solvent of EtOH: MeCN = 1: 5 was added, and the mixture was heated to 40 ° C. and stirred for 1 hour. The slurry was stirred for an hour. The solid obtained by filtration under reduced pressure was filtered and dried under reduced pressure to obtain 161 mg of white solid ((1) purified crystal) (yield 80%, HPLC purity 99.2%).
（10）Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ（Ａ）の合成（精製した（１）を使用）
１０ｍＬのナスフラスコにＤ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ塩酸塩（１）精製晶３８．５ｍｇ（０．０４８８ｍｍｏｌ）を仕込み、Ｈ2Ｏ ０．２ｍＬ（５．２ｖ／ｗ）を加え溶解させた。室温にて１Ｎ ＮａＯＨ １９７μＬ（０．１９７ｍｍｏｌ）を滴下して１．５ｈ撹拌した。反応終了後、１Ｎ ＨＣｌ ４８．８μＬ（０．０４８８ｍｍｏｌ）を加えエバポレーターにて減圧濃縮を行い、Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ（Ａ）を得た（収率ｑｕａｎｔ、ＨＰＬＣ純度９９．７％）。(10) Synthesis of D-Phe-D-Phe-D-Leu-D-Lys-Pic (A) (using purified (1))
D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe hydrochloride (1) 38.5 mg (0.0488 mmol) of purified crystals was charged into a 10 mL eggplant flask, and 0.2 mL of H 2 O (5 .2 v / w) was added and dissolved. At room temperature, 1N NaOH (197 μL, 0.197 mmol) was added dropwise and stirred for 1.5 h. After completion of the reaction, 48.8 μL (0.0488 mmol) of 1N HCl was added, and the mixture was concentrated under reduced pressure with an evaporator to obtain D-Phe-D-Phe-D-Leu-D-Lys-Pic (A) (yield). quant, HPLC purity 99.7%).
Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ（１）の物性
1H NMR(400MHz, 1M DCl) δ ppm : 0.85-1.02 (m, 6 H), 1.34-1.63 (m, 5 H), 1.65-2.12 (m, 5 H), 2.23-2.45 (m, 2 H), 2.96-3.12 (m, 4 H), 3.19 (ddt, J = 5.0 & 5.0 & 10.0 Hz), 3.33-3.62 (m, 1 H), 3.68-3.82 (m, 1 H), 3.82-3.95 (m, 4 H), 3.95-4.18 (m, 1 H), 4.25-4.37 (m, 2 H), 4.61-4.77 (m, 2 H), 7.21-7.44 (m, 10 H)
13C NMR(400MHz, 1M DCl) δ ppm : 21.8, 22.5, 24.8, 27.0, 30.5, 30.8, 31.0, 31.2, 31.7, 37.2, 37.8, 38.4, 39.0, 39.8, 40.4, 40.6, 41.8, 42.3, 49.8, 50.2, 52.2, 52.6, 54.6, 55.2, 57.7, 57.9, 127.6, 128.4, 129.2, 129.6, 129.7, 129.8
d.p 209.5℃Physical properties of D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe (1)
1 H NMR (400MHz, 1M DCl) δ ppm: 0.85-1.02 (m, 6 H), 1.34-1.63 (m, 5 H), 1.65-2.12 (m, 5 H), 2.23-2.45 (m, 2 H ), 2.96-3.12 (m, 4 H), 3.19 (ddt, J = 5.0 & 5.0 & 10.0 Hz), 3.33-3.62 (m, 1 H), 3.68-3.82 (m, 1 H), 3.82-3.95 ( m, 4 H), 3.95-4.18 (m, 1 H), 4.25-4.37 (m, 2 H), 4.61-4.77 (m, 2 H), 7.21-7.44 (m, 10 H)
13 C NMR (400MHz, 1M DCl) δ ppm: 21.8, 22.5, 24.8, 27.0, 30.5, 30.8, 31.0, 31.2, 31.7, 37.2, 37.8, 38.4, 39.0, 39.8, 40.4, 40.6, 41.8, 42.3, 49.8, 50.2, 52.2, 52.6, 54.6, 55.2, 57.7, 57.9, 127.6, 128.4, 129.2, 129.6, 129.7, 129.8
dp 209.5 ℃
実施例２
（トリフルオロ酢酸（ＴＦＡ）使用）
（１）Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ ＴＦＡ塩（１）の合成
５０ｍＬのナスフラスコにＴＦＡ １８ｍＬ（１８ｖ／ｗ）、１−ドデカンチオール１．６ｍＬ（１．６ｖ／ｗ）、トリイソプロピルシラン０．２ｍＬ（０．２ｖ／ｗ）、Ｈ2Ｏ ０．２ｍＬ（０．２ｖ／ｗ）を順次加え撹拌した。その溶液にＢｏｃ−Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（９）１．００ｇ（１．０１ｍｍｏｌ）をスパチュラで少量ずつ添加した。反応終了後、エバポレーターにて減圧濃縮を行い、得られた残渣をＩＰＥ ２０ｍＬ（２０ｖ／ｗ）に滴下した。析出した固体を濾別し、得られた固体を減圧乾燥して白色固体としてＤ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ・ＴＦＡ塩（１）を得た（収率９３．０％、ＨＰＬＣ純度９５．２％）。Example 2
(Use of trifluoroacetic acid (TFA))
(1) Synthesis of D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe TFA Salt (1) TFA 18 mL (18 v / w), 1-dodecanethiol 1.6 mL (1) in a 50 mL eggplant flask 1.6 v / w), 0.2 mL (0.2 v / w) of triisopropylsilane, and 0.2 mL (0.2 v / w) of H 2 O were sequentially added and stirred. To the solution, 1.00 g (1.01 mmol) of Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe (9) was added little by little with a spatula. After completion of the reaction, vacuum concentration was performed with an evaporator, and the obtained residue was added dropwise to 20 mL (20 v / w) of IPE. The precipitated solid was separated by filtration, and the obtained solid was dried under reduced pressure to obtain D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe.TFA salt (1) as a white solid (yield). Rate 93.0%, HPLC purity 95.2%).
（２）Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ（Ａ）の合成
１０ｍＬのナスフラスコにＤ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ ＴＦＡ塩（１）８３ｍｇ（０．０８４３ｍｍｏｌ）を仕込み、Ｈ２Ｏ ４３１μＬ（５．２ｖ／ｗ）を加えて溶解させた。室温にて１Ｎ ＮａＯＨ ３４５μＬ（０．３４５ｍｍｏｌ）を滴下して１２ｈ撹拌した。反応終了後、１Ｎ ＨＣｌ ８４．３μＬ（０．０８４３ｍｍｏｌ）を加えエバポレーターにて減圧濃縮を行い、Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ（Ａ）を得た（収率ｑｕａｎｔ、ＨＰＬＣ純度９５．４％）。(2) Synthesis of D-Phe-D-Phe-D-Leu-D-Lys-Pic (A) In a 10 mL eggplant flask, D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe TFA 83 mg (0.0843 mmol) of salt (1) was charged, and 431 μL (5.2 v / w) of H 2 O was added and dissolved. At room temperature, 345 μL (0.345 mmol) of 1N NaOH was added dropwise and stirred for 12 hours. After completion of the reaction, 84.3 μL (0.0843 mmol) of 1N HCl was added, and the mixture was concentrated under reduced pressure with an evaporator to obtain D-Phe-D-Phe-D-Leu-D-Lys-Pic (A) (yield). quant, HPLC purity 95.4%).
実施例３
（ＨＣｌ／ＥｔＯＡｃ使用）
（１）３０ｍＬのナスフラスコにＢｏｃ−Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（９）１．００ｇ（１．０１ｍｍｏｌ）を仕込み、ＥｔＯＡｃ７．０ｍＬ（７．０ｖ／ｗ）を加え溶解させた。４Ｎ ＨＣｌ／ＥｔＯＡｃ ５．０ｍＬ（５．０ｖ／ｗ）を加え室温で２４ｈ撹拌後、析出した固体を減圧濾過して濾別し、ＥｔＯＡｃ ２ｍＬ（２．０ｖ／ｗ）で洗浄した。得られた固体を減圧乾燥して白色固体としてＤ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ 塩酸塩（１）を７８１ｍｇ得た（収率９６．７％、ＨＰＬＣ純度９５．４％）。Example 3
(Using HCl / EtOAc)
(1) A 30 mL eggplant flask was charged with 1.00 g (1.01 mmol) of Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe (9). 7.0 mL (7.0 v / w) of EtOAc was added and dissolved. 4N HCl / EtOAc (5.0 mL, 5.0 v / w) was added, and the mixture was stirred at room temperature for 24 h. The precipitated solid was filtered off under reduced pressure and filtered, and washed with 2 mL (2.0 v / w) of EtOAc. The obtained solid was dried under reduced pressure to obtain 781 mg of D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe hydrochloride (1) as a white solid (yield 96.7%, HPLC purity). 95.4%).
（２）Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ（Ａ）の合成
１０ｍＬのナスフラスコにＤ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ 塩酸塩（１）９０ｍｇ（０．１１２ｍｍｏｌ）を仕込み、Ｈ2Ｏ ０．４７ｍＬ（５．２ｖ／ｗ）を加えて溶解させた。室温にて１Ｎ ＮａＯＨ ４５９μＬ（０．４５９ｍｍｏｌ）を滴下して１２ｈ撹拌した。反応終了後、１Ｎ ＨＣｌ ０．１１２μＬ（０．１１２ｍｍｏｌ）を加えエバポレーターにて減圧濃縮を行い、Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ（Ａ）を得た（収率ｑｕａｎｔ、ＨＰＬＣ純度９３．１％）。(2) Synthesis of D-Phe-D-Phe-D-Leu-D-Lys-Pic (A) In a 10 mL eggplant flask, D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe hydrochloric acid 90 mg (0.112 mmol) of salt (1) was charged, and 0.47 mL (5.2 v / w) of H 2 O was added and dissolved. At room temperature, 1N NaOH 459 μL (0.459 mmol) was added dropwise and stirred for 12 h. After the reaction was completed, 1N HCl (0.112 μL, 0.112 mmol) was added and the mixture was concentrated under reduced pressure using an evaporator to obtain D-Phe-D-Phe-D-Leu-D-Lys-Pic (A) (yield). quant, HPLC purity 93.1%).
実施例４
化合物（１）の加水分解による化合物（Ａ）の合成（化合物（１）の精製なし）
１０ｍＬのナスフラスコにＤ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ（１）塩酸塩（前工程精製なし）１１４．５ｍｇ（０．１４２ｍｍｏｌ）を仕込み、Ｈ2Ｏ ５９５μＬ（５．２ｖ／ｗ）を加え溶解させた。室温にて１Ｎ ＮａＯＨ ５８６μＬ（０．５８６ｍｍｏｌ）を滴下して１４ｈ撹拌した。反応終了後、１Ｎ ＨＣｌ ０．１５μＬ（０．１５０ｍｍｏｌ）を加えエバポレーターにて減圧濃縮を行い、Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ（Ａ）を得た（収率ｑｕａｎｔ、ＨＰＬＣ純度９５．２％）。Example 4
Synthesis of compound (A) by hydrolysis of compound (1) (without purification of compound (1))
In a 10 mL eggplant flask, 114.5 mg (0.142 mmol) of D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe (1) hydrochloride (no previous step purification) was charged, and 595 μL of H 2 O was added. (5.2 v / w) was added and dissolved. At room temperature, 586 μL (0.586 mmol) of 1N NaOH was added dropwise and stirred for 14 h. After completion of the reaction, 0.15 μL (0.150 mmol) of 1N HCl was added, and the mixture was concentrated under reduced pressure with an evaporator to obtain D-Phe-D-Phe-D-Leu-D-Lys-Pic (A) (yield) quant, HPLC purity 95.2%).
比較例１
化合物（１）を経由しない経路（全保護体Ｂｏｃ−Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（ａ）を使用）
（１）Ｂｏｃ−Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＨの合成
３０ｍＬのナスフラスコにＢｏｃ−Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＭｅ（９）１．００ｇ（１．００ｍｍｏｌ）を仕込み、ＭｅＯＨ ５．０ｍＬ（５．０ｖ／ｗ）を加えて溶解させた。室温にて１Ｎ ＮａＯＨ １．１ｍＬ（１．１０ｍｍｏｌ）を加えて４日間撹拌後、さらにＭｅＯＨ ５．０ｍＬ（５．０ｖ／ｗ）、１Ｎ ＮａＯＨ ２．０ｍＬ（２．０ｍｍｏｌ）を加えて３５℃で３ｈ撹拌した。反応終了後１Ｎ ＨＣｌ ６．１ｍＬを加え、減圧濃縮して溶媒を留去した後、ＥｔＯＡｃ ５．０ｍＬ（５．０ｍＬ）を加えて有機層を分液した。ＮａＣｌａｑ．５．０ｍＬ（５．０ｖ／ｗ）を加えて有機層を洗浄し、有機層を減圧濃縮して白色固体としてＢｏｃ−Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＨ ９７５．１ｍｇ（収率９９．３％、ＨＰＬＣ純度８０．８％）Comparative Example 1
Route not passing through compound (1) (using all-protected Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc) -α-Boc-Pic-OMe (a))
(1) Synthesis of Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc) -α-Boc-Pic-OH Boc-D-Phe-D-Phe-D- in a 30 mL eggplant flask 1.00 g (1.00 mmol) of Leu-D-Lys (Boc) -α-Boc-Pic-OMe (9) was charged, and 5.0 mL (5.0 v / w) of MeOH was added and dissolved. After adding 1.1 mL (1.10 mmol) of 1N NaOH at room temperature and stirring for 4 days, 5.0 mL (5.0 v / w) of MeOH and 2.0 mL (2.0 mmol) of 1N NaOH were further added at 35 ° C. Stir for 3 h. After completion of the reaction, 6.1 mL of 1N HCl was added, concentrated under reduced pressure to distill off the solvent, and then 5.0 mL (5.0 mL) of EtOAc was added to separate the organic layer. NaClaq. 5.0 mL (5.0 v / w) was added to wash the organic layer, and the organic layer was concentrated under reduced pressure to give Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc)-as a white solid. α-Boc-Pic-OH 975.1 mg (yield 99.3%, HPLC purity 80.8%)
（２）Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ（Ａ）の合成
２０ｍＬのナスフラスコにＢｏｃ−Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ（Ｂｏｃ）−α−Ｂｏｃ−Ｐｉｃ−ＯＨ（１０）９５９ｍｇ（０．９７８ｍｍｏｌ）を仕込み、ＥｔＯＡｃ ４．９ｍＬ（５．０ｖ／ｗ）を加えて溶解させた。室温にて４Ｎ ＨＣｌ／ＥｔＯＡｃ ４．９ｍＬ（５．０ｍＬ）を滴下して室温にて４ｈ撹拌した。反応終了後、減圧濾過して、白色固体としてＤ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ（Ａ）を得た（収率９６．４％、ＨＰＬＣ純度７９．２％）。(2) Synthesis of D-Phe-D-Phe-D-Leu-D-Lys-Pic (A) Boc-D-Phe-D-Phe-D-Leu-D-Lys (Boc) in a 20 mL eggplant flask -(Alpha) -Boc-Pic-OH (10) 959 mg (0.978 mmol) was prepared, and 4.9 mL (5.0 v / w) of EtOAc was added and dissolved. 4.9 mL (5.0 mL) of 4N HCl / EtOAc was added dropwise at room temperature, and the mixture was stirred at room temperature for 4 h. After completion of the reaction, filtration under reduced pressure gave D-Phe-D-Phe-D-Leu-D-Lys-Pic (A) as a white solid (yield 96.4%, HPLC purity 79.2%). .
本発明の化合物（１）を経由しなかった場合、得られる化合物（Ａ）の純度は８０％未満であった。 When not passing through the compound (1) of the present invention, the purity of the obtained compound (A) was less than 80%.
実施例５
（Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ塩酸塩（１）の合成）
前記実施例１の（８）において、反応溶媒ＩＰＡ（１．６５ｖ／ｗ）を、表１の溶媒と量に代えて同様に反応を行った。結果を表１に示す。Example 5
(Synthesis of D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe hydrochloride (1))
In Example 1 (8), the reaction was carried out in the same manner except that the reaction solvent IPA (1.65 v / w) was replaced with the solvent and amount shown in Table 1. The results are shown in Table 1.
実施例６
（Ｄ−Ｐｈｅ−Ｄ−Ｐｈｅ−Ｄ−Ｌｅｕ−Ｄ−Ｌｙｓ−Ｐｉｃ−ＯＭｅ塩酸塩（１）の精製）
前記実施例１の（９）において、精製溶媒ＥｔＯＨ／ＭｅＣＮ（１６．７：８３．５、２０ｖ／ｗ）を、表２の溶媒と量に代えて同様に反応を行った。結果を表２に示す。Example 6
(Purification of D-Phe-D-Phe-D-Leu-D-Lys-Pic-OMe Hydrochloride (1))
In (1) of Example 1 above, the reaction was carried out in the same manner except that the amount of the purified solvent EtOH / MeCN (16.7: 83.5, 20 v / w) was changed to the amount of solvent shown in Table 2. The results are shown in Table 2.
Claims (4)
で表される化合物又はその塩。The following formula (1)
Or a salt thereof.
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